A preventive pharmacotherapy for neonatal abstinence syndrome PROJECT SUMMARY/ABSTRACT Neonatal opioid dependence is an enormous and growing medical challenge. The goal of this study is to develop a drug therapy that can prevent opioid dependence in utero in order to suppress or reduce neonatal withdrawal (neonatal abstinence syndrome). The target population affected by this research is pregnant women under clinically controlled pain management or under clinical care for opioid dependence (such as methadone maintenance), and their babies. The proposed therapy must not interfere with management of maternal pain/dependence. To achieve this goal we are testing a peripherally-selective neutral antagonist of the mu-opioid receptor, 6?-naltrexol (6BN). We have shown in mice that the drug crosses the placenta and enters the fetal brain at high levels, but is relatively excluded from the maternal brain by the blood brain barrier (BBB). Thus our therapy takes advantage of the undeveloped fetal BBB. We have also shown that the drug enters the developing mouse brain at high levels until at least postnatal day 14, and that the drug can prevent early postnatal dependence behaviors at high potency when co-administered during morphine administration. The first goal of the proposal is to conduct a detailed pharmacokinetic (PK) analysis of 6BN and methadone (MTD) in pregnant mice (Aim 1A). Compartmental models will be developed to better assess and predict drug exposures. The second goal is to perform initial studies of the pharmacodynamics (PD) of 6BN and MTD in mice to determine a dose range of 6BN that prevents neonatal/juvenile dependence (no BBB), but does not affect maternal/adult pain alleviation (with BBB) (Aim 1B). The final goal is to translate the results in mice to a more appropriate model of the human neonatal developmental state: namely, rhesus monkey. A limited PK analysis will be initiated to determine if 6BN can be preferentially delivered to the fetal monkey brain as in mice, the core of the therapy (Aim 2). The project brings together a diverse team of basic researchers and clinicians with complementary skills, expertise, resources and experience to tackle this substantial societal problem.